Abstract
Multiple myeloma (MM) is characterised by destructive lytic bone disease, caused by induction of bone resorption and impaired bone formation. Our understanding of the molecular mechanisms responsible for osteoblast suppression, are limited. Using the 5T2MM murine model of MM we have previously shown that suppression of the activity of a known inhibitor of bone formation Dikkopf-1 (Dkk1) prevents the development of lytic bone disease. Here we have demonstrated that another potential inhibitor of bone formation, sclerostin domain containing 1 (Sostdc1) is expressed at low levels in MM and osteoblast lineage cells when these cells are grown separately in cell culture but its expression is significantly induced in both cell types when these cells are in contact. The distribution of Sostdc1 staining in bones infiltrated with 5TGM1 myeloma cells in vivo suggested its presence in both myeloma and osteoblast lineage populations when in close proximity. We have also shown that recombinant Sostdc1 inhibits both bone morphogenic proteins (BMP2 and 7) and Wnt signalling in primary osteoblasts and suppresses differentiation of these cells. Together, these findings suggest that Sostdc1 expression in 5TGM1-infiltrated bones as a result of the interaction between myeloma and osteoblast lineage populations, could result in suppression of osteoblast differentiation.
Highlights
Studies have shown that multiple myeloma (MM) cells arriving in bone occupy niches, where they interact with specific bone cell lineages [1,2,3]
In this study we aimed to identify other important factors involved in the development of myeloma-induced bone disease, using the Abbreviations: CTNNB1, β-catenin; BMP, bone morphogenetic protein; B2M, β-microglobulin; chr, chromosome; Dickkopf-related protein 1 (Dkk1), Dikkopf-1; DAB, diaminobenzidine; Frz, frizzled; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFP, green fluorescent protein; HGF, hepatocyte growth factor; HRP, horse radish peroxidase; IL, interleukin; LRP, lipoprotein-related protein; MM, multiple myeloma; OB, osteoblast; osteogenic media (OGM), osteogenic medium; Runx, runt-related transcription factor; SMAD, C. elegans SMA/Drosophila mothers against decapentaplegic homolog; Sostdc1, sclerostin domain containing 1; SOST, sclerostin; sFRP, secreted frizzled-related protein; Wnt, wingless-related integration site
Flow cytometric analysis of cell cultures showed that ~5% of the 5TGM1 cells and < 1% of the OB progenitors grown alone were Sostdc1 positive but this increased significantly to ~6% in the OB progenitors isolated from co-cultures (P = 0.043, Fig. 1A)
Summary
Studies have shown that multiple myeloma (MM) cells arriving in bone occupy niches, where they interact with specific bone cell lineages [1,2,3]. Myeloma cells held within niches are in a mitotically dormant state and this is maintained until they are released, leading to the development of lytic bone disease in 90% of patients [2]. Lytic bone disease associated with myeloma growth has, been extensively studied [4] and colonised bone is characterised by reduced osteoblastogenesis [5]. Antibodies to Dkk and SOST prevent the suppression of OB differentiation and the development of lytic bone disease in vivo [7,17]. There are likely to be other regulators that contribute to OB suppression in myeloma-induced bone disease [18]
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